Abstract Osteoporosis is a significant cause of morbidity and mortality in developed countries. In the United States, over 8 million women and 2 million men age 50 and above have osteoporosis. Another 51 million women and 35 million men have osteopenia. This translates into a higher risk of fracture within this population, with half of all women and one quarter of men projected to suffer a low bone mass-related fracture. Osteoporotic fractures impart deleterious consequences, including increased hospitalization and mortality. An estimated 25% of individuals will die within one year of a hip fracture. Despite the availability of anti-resorptive therapies that decrease fracture rates, their prescription and use have declined significantly due to fears of extremely rare but serious adverse events. This has created a treatment gap that threatens the quality of life of millions of Americans and poses a tremendous challenge to our healthcare systems and economy. It also highlights the need to better understand osteoclast formation and function. The goal of this five-year application is to determine the role of the protein phosphatase Phlpp1 in osteoclastogenesis and bone density and to define the epigenetic mechanisms required for Phlpp1 to modulate Csf1r (c-fms) expression and osteoclastogenesis. The five-year deliverables are: 1) definition of the functions of Phlpp1 in osteoclast progenitor cells, 2) characterization of the cytosolic functions of Phlpp1 that influence M-CSF responsiveness, Csfr1 expression and osteoclast function, and 3) determination of the nuclear functions of Phlpp1 that influence Csfr1 transcription and osteoclastogenesis. This work will increase our understanding of how Phlpp1 and associated pathways affect bone density.